3-(Omega-substituted alkyl)-indoles

ABSTRACT

3-(OMEGA-SUBSTITUTED ALKYL)-INDOLES ARE DISCLOSED WHICH ARE USEFUL IN AMELIORATING THE TREMORS OF Parkinsonism. The compounds are prepared by metal hydride reduction of the precursor indole glyoxyloyl compounds.

This application is a continuation-in-part of my copending applicationSer. No. 504,087 filed Oct. 23, 1965.

The present invention relates to certain heterocyclic organic compoundswhich may be referred to as 3-(omega-substituted alkyl)indoles, acidaddition and quaternary ammonium salts thereof, therapeutic compositionscontaining the same as active ingredients, and methods of making andadministering them.

The novel compounds of the present invention have utility asphysiologically active agents and are particularly effective indiminishing the tremors and muscular rigidity of Parkinsonism. Thecompounds are also useful as tranquilizers.

Prior art literature contains examples of 3-(omega-substitutedalkyl)indoles. Those which have been examined in animal bodies haveshown limited therapeutic value and are not disclosed to haveanti-Parkinson activity. More recently a series of 1-, 2-, and3-[2-(4-substituted piperazinyl)ethyl]indoles has been the subject ofU.S. Pat. 3,188,313 with the disclosure of their therapeutic applicationas CNS depressants. However, these are likewise not disclosed to haveanti-Parkinsonism activity.

Medicaments that have been used to ameliorate the symptoms ofParkinsonism have been derived from the belladonna group of alkaloids,particularly atropine and scopolamine; in addition synthetic medicinalssuch as Parsidol (TM), Artane (TM), Kemadrin (TM) and Disipal (TM) amongothers and certain antihistamine compounds have been used with varyingdegrees of success. Although all of the aforementioned drugs have beenof therapeutic value in treating the tremors and muscular rigidity ofParkinsonism, they have not been universally tolerated and the dosageshave had to be adjusted to the particular individual, and, moreover,these known drugs have produced various undesirable side effects.Examples of such side effects are dryness of mouth, nausea, giddiness,blurred vision, nervousness, tinnitus, sore mouth, mental confusion,marked agitation, epigastric burning, heavy feeling in the limbs orsensations of tingling in them, disorientation, anorexia and transientpsychotic episodes. Anti-Parkinsonism agents eliminating or reducing thedegree of any of the foregoing side effects are, therefore, highlydesirable.

It is accordingly the primary object of the present invention to providenovel compounds that are useful in the palliative treatment ofParkinsonism, and particularly to provide compounds useful asanti-Parkinsonism agents and which produce minimal side effects. Furtherobjects are to provide a method of using said drugs in the treatment ofliving animal and especially mammalian bodies, to provide pharmaceuticalcompositions which embody the said agents, and to provide a method forpreparing said novel 3-(omega-substituted alkyl)indoles. Additionalobjects will be apparent to one skilled in the art and still furtherobjects will become apparent hereinafter.

The novel compounds of the present invention can be represented by thefollowing formula: ##SPC1##

wherein:

R is selected from the group consisting of hydrogen, lower-alkyl,lower-alkanoyl, aroyl, monocarbocyclic aryl, phenyl-lower-alkyl andcycloalkyl; R₁ is selected from the group consisting of hydrogen,lower-alkyl and monocarbocyclic aryl; R₂ is selected from the groupconsisting of hydrogen, halogen having an atomic weight less than 80,trifluoromethyl, hydroxyl, lower-alkoxy and aralkoxy; R₃ is selectedfrom the group consisting of hydrogen and methyl, no more than onemethyl being present at one time; R₄ is selected from the groupconsisting of hydrogen, lower-alkyl, phenyl-lower-alkyl andmonocarbocyclic aryl; A is selected from the group consisting ofhydrogen, lower-alkanoyl, monocarbocyclic aryl, monocarbocyclic aroyland monocarbocyclic aryl carbamoyl; n is an integer from 0-4 inclusive;m is either zero or one; p is either zero or one, and when p is zero thedotted line represents a double bond.

In the definition of symbols in the foregoing Formula I and where theyappear elsewhere throughout this specification, the terms have thefollowing significance.

The term "lower-alkyl" as used herein includes straight and branchedchain radicals of up to eight carbon atoms inclusive and is exemplifiedby such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, amyl, isoamyl, hexyl, heptyl, octyl, and the like."Lower-alkoxy" has the formula--O--lower-alkyl.

The term "cycloalkyl" as used herein includes primarily cyclic alkylradicals containing three up to nine carbon atoms inclusive andencompasses such groups as cyclopropyl, cyclobutyl, cyclopentyl,methylcyclohexyl, ethylcyclopentyl, and propylcyclohexyl. Included inthe term "phenyl lower alkyl" are groups such as benzyl, phenethyl,methylbenzyl, phenpropyl and the like. "Lower-alkanoyl" has the formula##EQU1## "Aroyl" has the formula ##EQU2## and "aralkoxy" has theformula: --O--lower-alkyl-monocarbocyclic aryl.

By monocarbocyclic aryl is meant a phenyl radical or a phenyl radicalsubstituted by one or more substituents selected from the groupconsisting of halogen having an atomic weight less than 80, lower-alkyl,lower-alkoxy and trifluoromethyl. The lower-alkyl and lower-alkoxyradicals can contain up to three carbon atoms and each monocarbocyclicaryl radical, together with said substituents, can contain from six tonine carbon atoms. When the monocarbocyclic aryl radical is substitutedby more than one of the above substituents, the substituent can be thesame or different and can occupy any of the available positions on thephenyl ring. When the substituent is lower-alkyl, said constituent canbe straight or branched and can contain from one to three carbon atoms.Thus when R represents a monocarbocyclic aryl radical it can representan organic radical such as phenyl or a phenyl radical substituted by oneor more substituents such as fluoro, chloro, bromo, methyl, isopropyl,methoxy, propoxy or trifluoromethyl. A total of nine carbon atoms in allring substituents is the preferred maximum.

This invention also included acid addition salts of the above definedbases formed with nontoxic organic and inorganic acids. Such salts areeasily prepared by methods known in the art. When the compounds are tobe used as intermediates for preparing other compounds or for any othernon-pharmaceutical use, the toxicity or nontoxicity of the salt isimmaterial; when the compounds are to be used as pharmaceuticals, theyare most conveniently used in the form of nontoxic acid-addition orquaternary ammonium salts. Both toxic and nontoxic salts are thereforewithin the purview of the invention. The acids which can be used toprepare the preferred nontoxic acid-addition salts are those whichproduce, when combined with the free bases, salts whose anions arerelatively innocuous to the animal organism in therapeutic doses of thesalts, so that beneficial physiological properties inherent in the freebases are not vitiated by side-effects ascribable to the anions.

The base is reacted with the calculated amount of organic or inorganicacid in aqueous miscible solvent, such as ethanol or ispropanol, withisolation of the salt by concentration and cooling, or the base isreacted with an excess of the acid in aqueous immiscible solvent, suchas ethyl ether or isopropyl ether, with the desired salt separatingdirectly. Exemplary of such organic salts are those with maleic,fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic, acetic,propionic, tartaric, citric, lactic, malic, citraconic, itaconic,hexamic, p-aminobenzoic, glutamic, stearic acid and the like. Exemplaryof such inorganic salts are those formed with hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, and nitric acids.

In addition, this invention includes pharmaceutically acceptable,nontoxic quaternary ammonium salts of the above defined bases. Thequaternary ammonium salts are readily formed by treatment of thecorresponding free base with the appropriate salt-forming substance,including, for example, methyl chloride, methyl bromide, methyl iodide,methyl sulfate, ethyl chloride, ethyl bromide, ethyl iodide, n-propylchloride, n-propyl bromide, n-propyl iodide, isobutyl iodide, sec-butylbromide, n-amyl chloride, n-amyl bromide, n-amyl iodide, isoamylchloride, n-hexyl chloride, n-hexyl bromide, n-hexyl iodide or similarquaternary salt-forming substances, according to general procedureswhich are well known in the art.

It will be readily apparent to one skilled in the art that certaincompounds of this invention may be present as optical isomers. Theconnotation of the general formulas presented herein is to include allisomers, the separated d or l isomers as well as the dl mixtures ofthese isomers.

In general, the novel compounds of this invention are prepared startingfrom readily available selected indoles or from indoles prepared by theFischer indole synthesis. The indoles are reacted with oxalyl chlorideat 0°-25° C. according to the procedure of Speeter and Anthony, J. Am.Chem. Soc. 76, 6208-10 (1954) in an organic solvent inert under theconditions of the reaction, such as ether, dioxane, and the like to giveindole-3-glyoxyoyl chloride. The preferred solvent is ether.

Preparation of the novel compounds of the invention which contain a4-substituted piperidine or a 3-substituted pyrrolidine moiety iseffected by reacting the appropriate piperidine and pyrrolidinecompounds with an appropriately substituted indole-3-glyoxyloyl chloridein a suitable solvent such as benzene, chloroform, dioxane, toluene,acetonitrile and the like, which will not enter into the reaction butwhich will provide a reaction medium. An acid acceptor which may be anexcess amount of the reacting heterocyclic compound, a tertiary amine oran alkali metal salt of a weak acid may be used, the alkali metal saltof a weak acid, e.g., sodium carbonate, sodium bicarbonate, potassiumcarbonate, and the like being the preferred acid acceptors. It wasobserved that indole-3-glyoxyloyl chloride is not readily hydrolyzed bywater at or about room temperature and in an alternative procedure thereaction between an indole-3-glyoxyloyl chloride and the selectedsubstituted piperidine or pyrrolidine can be conveniently carried out ina chloroform-water mixture. The alternate method is particularlyconvenient when the acid acceptor employed is an alkali metal salt of aweak acid. The purpose of the acid acceptor is to take up the hydrogenhalide which is split out during the course of the reaction. Thereaction is conveniently carried out at or about room temperature for aperiod of about 3 to 5 hours. Isolation of the product, a1-(indole)-3-ylglyoxyl)-3-substituted pyrrolidine or 4-substitutedpiperidine, is achieved by dilution of the reaction mixture with water,separation of the organic and aqueous layers, and drying andconcentration of the organic layer. The crude products are best purifiedby crystallization from a suitable solvent, chromatography or formationof a readily crystallizable organic or inorganic salt.

Reduction of the 1-(indol-3-ylglyoxyloyl)-3-substituted pyrrolidines and4-substituted piperidines to the novel 3-[2-(3-substitutedpyrrolidinyl)ethyl]indoles and 3-[2-(4-substitutedpiperidinyl)ethyl]indoles of the present invention is achieved by metalhydride reduction in an anhydrous organic solvent including, forexample, ether, tetrahydrofuran, benzene, toluene, ethylene glycol,dimethyl ether, and the like. Metal hydrides generally used forreduction of carbonyl groups include lithium aluminum hydride, sodiumborohydride, potassium borohydride, sodium borohydride-aluminumchloride, diisobutylaluminum hydride and the like. Lithium aluminumhydride is the preferred metal hydride. The compound to be reduced isdissolved or suspended in an anhydrous solvent and added dropwise, undernitrogen, to a stirred suspension of a metal hydride in an organicsolvent. After refluxing the stirred reaction mixture for about 2 to 5hours, the reaction mixture is worked up and the product separated byprocedures well known in the art.

Preparation of the novel compounds of the invention which contain4-substituted-3,4-dehydropiperidine and 3-substituted-3,4-pyrrolinemoieties can be carried out by alternate procedures. As one preparativemethod a 4-substituted-4-piperidinol is reacted with anindole-3-glyoxyloyl chloride and the resulting compound reduced by metalhydride combination to furnish the reduced compound as in thepreparation of 3-[2-(4-hydroxy-4-phenylpiperidinyl)ethyl]indole.Dehydration of the latter compound under mildly acidic conditionsfurnishes 3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl] indole. In asecond, preferred preparative method, a 4-substituted-4-piperidinol isdehydrated under mildly acidic conditions to a4-substituted-3,4-dehydropiperidine which is reacted with anindole-3-glyoxyloyl chloride and the resulting1-(indol-3-ylglyoxyloyl)-4-substituted- 3,4 -dehydropiperidine reducedby metal hydride combination to a3-[2-(4-substituted-3,4-dehydropiperidinyl)ethyl]indole.

Dilute hydrochloric acid is generally used as a dehydrating agent. Otheracids can be used equally well and are within the purview of thisinvention including, for example, hydrochloric acid-acetic acid,phosphoric acid, concentrated and dilute sulfuric acid, benzenesulfonicacid and p-toluenesulfonic acid.

The novel indole compounds may be purified by vacuum distillation or bycrystallization of their well-defined organic or inorganic salts.

Preparation of the novel compounds of the present invention is notrestricted to the preceding described methods but can also be preparedby alternative procedures. In one alternative method appropriatelysubstituted indole-3-acetic acids are prepared from appropriatelysubstituted hydrazones by the Fischer indole synthesis. The substitutedindole-3-acetic acids are esterified by conventional esterificationprocedures and the esters reduced by metal hydrides to the correspondingsubstituted 3-(2-hydroxyethyl)indoles. Reaction of the latter with athionyl halide furnishes a substituted 3-(2-haloethyl)indole, thegaseous by-products sulfur dioxide and hydrogen halide being removedfrom the reaction system by application of a slight vacuum or bysweeping the by-product gases out of the reaction system by the use ofan inert gas, as, for example, nitrogen. The substituted3-(2-hydroxyethyl)indoles can also be converted to their arylsulfonateesters by reaction with benzenesulfonyl chloride or p-toluenesulfonylchloride in an inert organic solvent as, for example, benzene. Bytreating the resulting substituted 3-(2-hydroxyethyl)indoles or thearylsulfonate esters of the substituted 3(2-hydroxyethyl)-indoles with a3-substituted pyrrolidine, a 4-substituted piperidene, a3-substituted-3,4-pyrroline or a 4-substituted-3,4-dehydropiperidine inthe presence of a suitable acid acceptor which may be a molar excess ofthe organic base, a tertiary amine or an alkali metal salt of a weakacid, the desired 3-[2-(3 -substituted pyrrolidinyl)ethyl]indoles,3-[2-(4-substituted piperidinyl)ethyl]indoles, 3[2-(3-substituted-3,4-pyrroline)ethyl]indoles and 3-[2-(4-substituted-3,4-dehydropiperidinyl)ethyl]indoles are obtained.

PREPARATION OF INTERMEDIATES Preparation 1

1 -inol- 3-ylglyoxylolyl)-3-(o-methoxyphenoxy)-pyrrolidine.--To astirred mixture of 11.5 g. (0.06 mole) of3-(o-methoxyphenoxy)-pyrrolidine and 10 g. of sodium carbonate in 100ml. of chloroform and 35 ml. of water was added slowly over a ten minuteperiod 11.5 g. (0.056 mole) of indole-3-glyoxyloyl chloride. Afterstirring one hour 25 ml. of water was added and stirring continued anadditional two hours. The organic layer was separated and washedsuccessively with water, 3 N hydrochloric acid, water and 3 N sodiumhydroxide. The chloroform solution was dried over magnesium sulfate andconcentrated leaving a viscous oil which solidified on standing. Thesolid was suspended in hot benzene and treated with absolute ethanoluntil solution of the solid occurred. After concentrating the solutionto two-thirds of the original volume, isooctane was added to the hotsolution. After cooling 17.0 g. (83%) of product separated, M.P.173°-176° C. Recrystallization from the same solvent system raised themelting point to 175-177° C.

Analysis.--Calculated for C₂₁ H₂₀ N₂ O₄ (percent): C, 69.21; H, 5.53; N,7.69. Found (percent): C, 69.55; H, 5.57; N, 7.99.

Preparation 2

1 -[ (2-methylindol-3-yl)glyoxyloyl]-3-hydroxypyrrolidine.--3-pyrrolidinol(12.5 g; 0.144 mole) was added dropwise over a 30 minute period to avigorously stirred mixture of 32 g. (0.144 mole) of2-methylindole-3-glyoxyloyl chloride, 40 g. of sodium carbonate and 400ml. of dry benzene. After stirring 24 hours at room temperature, 200 ml.of water was added, the original solid suspension changing to a red gum.After standing several days in benzene the red gum solidified to a redsolid melting at 180°-190° C. The melting point could not be improvedbut thin layer chromatography indicated the material to be quite pure.The yield was 25.0 g. (64%).

Preparation 3

1-[5,6-dimethoxyindol- 3 -yl)glyoxyloyl]-3-hydroxypyrrolidine.--(a) To astirred mixture of 8.0 g. (0.03 mole) of5,6-dimethoxyindole-3-glyoxyloyl chloride, 5 g. of sodium carbonate, 25ml. of water and 75 ml. of chloroform was added 2.6 g. (0.03 mole) of3-pyrrolidinol. After stirring one hour at room temperature the mixturewas filtered and the cake washed with water and then chloroform. Thedried product weighed 4.05 g. (42%) and melted at 224°-226° C.Recrystallization from methanol-water raised the melting point to229°-231° C.

Analysis.--Calculated for C₁₆ H₁₈ N₂ O₅ (percent): C, 60.37; H, 5.70; N,8.80. Found (percent): C, 60.32; H, 5.76; N, 9.34.

(b) 3-pyrrolidinol (0.95 g.; 0.01 mole) was added to a stirred mixtureof 2.9 g. (0.01 mole) of 5,6-dimethoxyindole-3-glyoxyloyl chloride, 4.0g. of sodium carbonate and 100 ml. of benzene. After stirring overnightat room temperature, 50 ml. of water was added. The mixture was stirred30 minutes, filtered and the cake washed with water and then withbenzene. The dried material weighed 1.45 g. (45%) and melted at222°-225° C.

Preparation 4

1-(indol- 3 -ylglyoxyloyl)-3-hydroxypyrrolidine.--A solution of 1.25 g.(0.014 mole) of 3-pyrrolidinol and 3.0 g. of sodium carbonate in 35 ml.of water was treated all at once with 3 g. (0.014 mole) ofindole-3-glyoxyloyl chloride and the mixture stirred at room temperaturefor 24 hours. The product was isolated by filtration and recrystallizedfrom absolute alcohol. The yield was 2.6 g. (70%) and the materialmelted at 216°-218° C.

Analysis.--Calculated for C₁₄ H₁₄ N₂ O₃ (percent): C, 65.10; H, 5.46; N,10.85. Found (percent): C, 65.19; H, 5.48; N, 10.97.

Preparation 5

1-[(2,5-dimethylindol- 3-yl)glyoxyloyl]-4-phenyl-3,4-dehydropiperidine.--2.5dimethylindole-3-glyoxyloyl chloride (9.5 g.; 0.0405 mole) was added, inportions, to a stirred mixture of 9.8 g. (0.05 mole) of4-phenyl-3,4-dehydropiperidine hydrochloride, 25 g. of potassiumcarbonate, 150 ml. of chloroform and 100 ml. of water. After stirring 30minutes the layers were separated, the aqueous layer extracted severaltimes with chloroform, the combined chloroform solutions dried overmagnesium sulfate and concentrated to an oil. Crystallizaton of the oilfrom ethanol-water gave 8.5 g. (59%) of product melting at 179°-182° C.An analytical sample recrystallized from the same solvent system meltedat 182°-184° C.

Analysis.--Calculated for C₂₃ H₂₁ N₂ O₂ (percent): C, 77.29; H, 5.92; N,7.84. Found (percent): C, 76.94; H, 6.32; N, 7.81.

Preparation 6

1-(indol-3-ylglyoxyloyl)- 4 -phenyl-3,4-dehydropiperidine.--To avigorously stirred mixture of 82.0 g. (0.42 mole) of4-phenyl-3,4-dehydropiperidine hydrochloride, 87.5 g. of potassiumcarbonate, 350 ml. of chloroform and 350 ml. of water was added inportions 79 g. (0.381 mole) of indole-3-glyoxyloyl chloride. Chloroform(250 ml.) and 150 ml. of water was added during the addition to keep thereaction mixture fluid. After stirring 30 minutes the reaction mixturewas filtered, the cake washed thoroughly with water and dried; the driedsolid weighed 121 g. and melted at 192°-194° C. Recrystallization of thesolid from acetonitrile gave 101.2 g. of material melting at 194°-196°C. Work-up of the filtrates gave additional material giving a totalyield of 114.7 g. (90%).

Preparation 7

1-[(2-methylindol-3-yl)glyoxyloyl] -4-phenyl-3,4-dehydropiperidine.--Using the method of preparation 5, 18.7g. (0.095 mole) of 4-phenyl-3,4-dehydropiperidine hydrochloride, 19.0 g.(0.086 mole) of 2-methylindole-3-glyoxyloyl chloride and 30 g. ofpotassium carbonate were mixed and reacted together in achloroform-water medium to give 21.3 g. (72%) of1-[(2-methylindol-3-yl)glyoxyloyl]- 4 -phenyl-3,4-dehydropiperidinemelting at 165°-167° C.

Analysis.--Calculated for C₂₂ H₂₀ N₂ O₂ (percent): C, 76.72; H, 5.85; N,8.13. Found (percent): C, 76.75; H, 5.89; N, 8.14.

Preparation 8

1-[(5-chloroindol- 3-yl)glyoxyloyl]-4-phenyl-3,4-dehydropiperidine.--Using the method ofpreparation 5, 13.0 g. (0.073 mole) of 4-phenyl-3,4-dehydropiperidinehydrochloride, 16.0 g. (0.066 mole) of 5-chloroindole-3-glyoxyloylchloride and 18 g. (0.182 mole) of triethylamine were mixed and reactedtogether using chloroform as a solvent in a nitrogen atmosphere to give11.6 g. (48.5%) of1-[(5-chloroindol-3-yl)glyoxyloyl]-4-phenyl-3,4-dehydropiperidinemelting at 200°-202° C. after crystallization from ethanol-water.

Analysis.--Calculated for C₂₁ H₁₇ ClN₂ O₂ (percent): C, 69.13; H, 4.70;N, 7.68. Found (percent): C, 68.83; H, 4.57; N, 7.71.

Preparation 9

1-[(5-benzyloxyindol- 3 -yl)glyoxyloyl]-4-phenyl-4-piperindol.--Usingthe method of preparation 5, 21 g. (0.12 mole) of4-phenyl-4-piperidinol, 36 g. (0.11 mole) of5-benzyloxyindole-3-glyoxyloyl chloride and 17 g. (0.17 mole) oftriethylamine were mixed and reacted together using chloroform as asolvent to give 33.5 g. (66%) of 1-[(5 -benzyloxyindol- 3-yl)glyoxyloyl]-4-phenyl-4-piperindol melting at 160°-163° C. (fromethanol-water). An analytical sample recrystallized from ethanol meltedat 155°-157° C.

Analysis.--Calculated for C₂₈ H₂₆ N₂ O₂ (percent): C, 73.99; H, 5.77; N,6.16. Found (percent): C, 73.59, H, 5.74; N, 6.16.

Preparation 10

1-[(5,6-dimethoxyindol-3-yl)glyoxyloyl]-4-phenyl-3,4-dehydropiperidine.--Using the method ofpreparation 5, 6.65 g. (0.034 mole) of 4-phenyl-3,4-dehydropiperidinehydrochloride, 8.2 g. (0.0307 mole) of 5,6-dimethoxyindol-3-glyoxyloylchloride and 15 g. of potassium carbonate were mixed and reactedtogether in a chloroform-water medium to give 7.9 g. (65%) of1-[(5,6-dimethoxyindol-3-yl)glyoxyloyl]- 4 -phenyl-3,4-dehydropiperidinemelting at 234°-237° C. An analytical sample crystallized fromacetonitrile melted at 236°-239° C.

Analysis.--Calculated for C₂₃ H₂₂ N₂ O₄ (percent): C, 70.75; H, 5.68; N,7.18. Found (percent): C, 70.55; H, 5.85; N, 7.18.

Preparation 11

1 -[(2-methyl-5,6-dimethoxyindol-3-yl)glyoxyloyl]-4-phenyl-3,4-dehydropiperidine.--Usingthe method of preparation 5, 12.4 g. (0.064 mole) of4-phenyl-3,4-dehydropiperidine hydrochloride, 16.2 g. (0.055 mole) of2-methyl-5,6-dimethoxyindol-3-glyoxyloyl chloride and 15.9 g. (0.159mole) of triethylamine were mixed and reacted together using chloroformas a solvent in a nitrogen atmosphere. The isolated crude product wascrystallized from benzene to give 18.1 g. of solid melting at 108°-111°C. A nuclear magnetic resonance spectrum indicated the solid to be abenzene solvate in a 1:1 ratio. An analytical sample recrystallized frombenzene melted at 104°-106° C.

Preparation 12

1 -[(1 -methylindol- 3-yl)glyoxyloyl]-4-phenyl-3,4-dehydropiperidine.--Twenty grams (0.061mole) of 1 -(indol-3-ylglyoxyloyl)-4-phenyl-3,4-dehydropiperidine wasdissolved in 350 ml. of 2-butanone maintained just below the refluxtemperature. While maintaining vigorous stirring, 25 g. of potassiumhydroxide was added in one portion followed immediately by the dropwiseaddition of 19.8 g. (0.14 mole) of methyl iodide. Five minutes after thecompletion of the addition, the reaction mixture was filtered and thefiltrate concentrated to an oil which solidified on standing.Recrystallization of the solid from ethyl acetate-isooctane gave 18.5(92%) of product melting at 173°-176° C. An analytical samplerecrystallized from acetone-water melted at 173°-175° C.

Analysis.--Calculated for C₂₂ H₂₀ N₂ O₂ (percent): C, 76.72; H, 5.85; N,8.13. Found (percent): C, 76.71; H, 5.80; N, 8.16.

Preparation 13

1 -(indol- 3 -ylglyoxyloyl)- 4-phenyl-4-piperindol.--A solution of 17.7g. (0.01 mole) of 4-phenyl-4-piperidinol in 100 ml. of chloroform wasadded to a solution of 25 g. of potassium carbonate in 100 ml. of water.The resulting heterogeneous mixture was stirred vigorously while 20 g.of indole-3-glyoxyloyl chloride was added portionwise over severalminutes. The mixture was stirred two hours and then the resultingprecipitate was filtered off and washed with chloroform and water (34g.). The product was dissolved in hot ethyl acetate, filtered, andtreated with isooctane. After cooling, 18.6 g. (55%) of pure product wasobtained which melted at 199°-201° C. Further recrystallization did notraise the melting point.

Analysis.--Calculated for C₂₁ H₂₀ N₂ O₃ (percent): C, 72.39; H, 5.79; N,8.04. Found (percent): C, 72.12; H, 5.97; N, 8.17.

Preparation 14

1 -(indol- 3-ylglyoxyloyl)-4-(m-trifluoromethylphenyl)-4-piperindol.--Indole-3-glyoxyloylchloride (18.5 g.; 0.089 mole) was added in portions to a stirredmixture of 25 g. (0.089 mole) of4-(m-trifluoromethylphenyl)-4-piperidinol, 30 g. of potassium carbonate,100 ml. of chloroform and 100 ml. of water. After stirring 0.5 hour theorganic layer was separated and the aqueous layer extracted withchloroform. The combined organic layer and chloroform extract was driedand concentrated to give 44.2 g. of oil. Thin layer chromatographyindicated only a small amount of impurity was present in the oil.

Preparation 15

4 -(m-trifluoromethylphenyl)- 3,4-dehydropiperidine hydrochloride.--Asolution of 15 g. (0.0535 mole) of4-(m-trifluoromethylphenyl)-4-piperidinol hydrochloride in 75 ml. of 6 Nhydrochloric acid was refluxed 3 hours, the solution cooled, neutralizedwith 3 N sodium hydroxide and extracted several times with chloroform.The combined extracts were dried and concentrated to an oil (13.4 g.).The oil was treated with ethereal hydrogen chloride to give 11.8 g.(84%) of the hydrochloride melting at 204°-206° C. after crystallizationfrom isopropanol. An analytical sample recrystallized from isopropanolmelted at 205°-207° C.

Analysis.--Calculated for C₁₂ H₁₃ ClF₃ N (percent): C, 54.65; H, 4.97;N, 5.31. Found (percent): C, 54.87; H, 5.04; N, 5.60.

Utilizing the method of preparation 1, the following compounds areprepared from the stated starting material:

1-[ (1 -phenylindol-3-yl)glyoxyloyl]-4-benzyl-4-piperidinol from1-phenylindole-3-glyoxyloyl chloride and 4-benzyl-4-piperidinol.

1-[ (2 -phenylindol-3-yl)glyoxyloyl]-4-phenyl-4-piperidinol from2-phenylindole-3-glyoxyloyl chloride and 4-phenyl-4-piperidinol.

1-[ (1 -benzylindol-3-yl)glyoxyloyl]-3-methyl-4-phenyl-4-piperidinolfrom 1-benzylindole-3-glyoxyloyl chloride and3-methyl-4-phenyl-4-piperidinol.

1-[ (1 -cyclohexyl- 3-yl)glyoxyloyl]-3-methyl-4 -phenyl- 4 -piperidinolfrom 1-cyclohexylindole-3-glyoxyloyl chloride and3-methyl-4-phenyl-4-piperidinol.

1 -(indol- 3 -ylglyoxyloyl)- 4 -o-tolyl-4-piperidinol fromindole-3-glyoxyloyl chloride and 4-o-tolyl-4-piperidinol.

1 -(indol- 3 -ylglyoxyloyl)-3-methyl-4-o-tolyl-4-piperidinol fromindole-3-glyoxyloyl chloride and 3-methyl-4-o-tolyl-4-piperidinol.

1-[ (6 -trifluoromethylindol- 3-yl)glyoxyloyl]-4-phenyl-4-piperidinolfrom 6-trifluoromethylindole-3-glyoxyloyl chloride and4-phenyl-4-piperidinol.

The examples below illustrate in detail some of the compounds whichcomprise this invention and methods for their production. However, thisinvention is not to be construed as limited thereby in spirit or inscope. It will be apparent to one skilled in the art that numerousmodifications in materials and methods can be adopted without departingfrom the invention.

EXAMPLE 1 3-[2-(3-hydroxypyrrolidinyl)ethyl]indole

A suspension of 11 g. (0.043 mole) of1-(indol-3-ylglyoxyloyl)-3-pyrrolidinol in 50 ml. of tetrahydrofuran wasadded dropwise, under nitrogen, to a stirred suspension of 9.8 g. (0.026mole) of lithium aluminum hydride in 100 ml. of tetrahydrofuran. Afteraddition, the mixture was refluxed for 2 hours, cooled, and treated withenough water to destroy the excess lithium aluminum hydride. Theresulting aluminum hydroxide was filtered off and washed thoroughly withtetrahydrofuran. The filtrate was evaporated on a rotating evaporator toan oil which solidified on standing. Crystallization from acetonitrilegave a melting point of 144°-146° C.; yield 7.7 g. (78%).

Analysis.--Calculated for C₁₄ H₁₈ N₂ O (percent): C, 73.01; H, 7.88; N,12.16, Found (percent): C, 72.80; H, 7.94; N, 12.20.

EXAMPLE 2 2-methyl-3-{2-[3-(3,4,5-trimethoxybenzoyloxy)pyrrolidinyl]ethyl}indole

To a suspension of 5 g. (0.02 mole) of2-methyl-3-[2-(3-hydroxypyrrolidinyl)ethyl]indole and 8 g. (0.075 mole)of sodium carbonate in 40 ml. of chloroform was added 4.2 g. (0.018mole) of 3,4,5-trimethoxybenzoyl chloride in 30 ml. of chloroform. Themixture was stirred under anhydrous conditions for 24 hours, thentreated with 25 ml. of water and stirred an additional hour. Thechloroform layer was separated, dried over magnesium sulfate andevaporated on a rotating evaporator to a viscous oil.

The oil was chromatographed on a magnesium silicate column (60-100 mesh)and eluted with benzene, then benzene with increasing amo unts ofacetone. Pure produce began eluting with 10% acetone-benzene; yield 6.2g. (79%). The pure oil slowly crystallized from ethanol giving 4.8 g. ofcrystalline solid melting at 119°-121° C.

Analysis.--Calculated for C₂₅ H₃₀ N₂ O₅ (percent): C, 68.47; H, 6.90; N,6.39. Found (percent): C, 68.41; H, 7.10; N, 6.22.

EXAMPLE 3 2-methyl-3-[2-(3-hydroxypyrrolidinyl)ethyl]indolehydrochloride

A suspension of 24 g. (0.088 mole) of1-[2-methylindol-3-yl)glyoxyloyl]-3-pyrrolidinol in 100 ml. oftetrahydrofuran was added dropwise with stirring under a nitrogenatmosphere to 15 g. (0.40 mole) of lithium aluminum hydride in 200 ml.of tetrahydrofuran. After addition the mixture was refluxed for 3 hours,cooled and the excess lithium aluminum hydride destroyed carefully withwater. The mixture was filtered and the aluminum hydroxide washedthoroughly several times with tetrahydrofuran. Evaporation of thecombined filtrates gave an oil which would not crystallize. The oil wasdissolved in acetone and treated with dry HCl gas. On cooling 18.5 g. ofimpure product precipitated. Recrystallization fromisopropanol-acetonitrile (90:10) gave 13 g. (52%) of pure productmelting at 208°-209° C.

Analysis.--Calculated for C₁₅ H₂₁ ClN₂ O (percent): C, 64.16; H, 7.54;N, 9.98. Found (percent): C, 64.37; H, 7.98; N, 9.72.

EXAMPLE 4 3-{2-[3-(3,4,5-trimethoxybenzoyloxy)pyrrolidinyl] ethyl}indole

A mixture of 3 g. (0.013 mole) of3-[2-(3-hydroxypyrrolidinyl)ethyl]indole, 3 g. (0.013 mole) of3,4,5-trimethoxybenzoyl chloride and 5 g. (0.05 mole) of sodiumcarbonate in 40 ml. of chloroform was stirred under anhydrous conditionsfor 24 hours. Then 0.3 g. of additional acid chloride was added and themixture stirred another 24 hours. The mixture was treated with 50 ml. ofwater, stirred for 1 hour and the chloroform layer separated and driedover magnesium sulfate. Evaporation of the chloroform on a rotatingevaporator gave an oil which would not crystallize.

The product was chromatographed on a magnesium silicate column (60-100mesh) and eluted with benzene, then benzene with increasing amounts ofacetone. At 10% acetone-benzene pure product began to elute from thecolumn; yield 4.3 g. (78%). The glassy solid could be crystallized frombenzene or benzene-ligroin giving a solid which melted between 79° and86° with gas evolution. Analysis as well as the infrared spectrumindicated that the solid was a benzene solvate.

Analysis.--Calculated for C₃₀ H₃₄ N₂ O₅ * (percent): C, 71.69; H, 6.82;N, 5.57. Found (percent): C, 71.46; H, 6.77; N, 5.94.

EXAMPLE 5 3-{2-[3-(3,4,5-trimethoxyphenylcarbamoyloxy)pyrrolidinyl]ethyl}indole

A suspension of 3 g. (0.013 mole) of3-[2-(3hydroxypyrrolidinyl)ethyl]indole and 3.05 g. (0.013 mole) of3,4,5-trimethoxybenzoyl azide in 40 ml. of dry benzene was refluxedunder nitrogen for 8 hours during which time the suspension slowlydissolved. Removal of the solvent under vacuum gave a dark glassy solidwhich would not crystallize. The material was dissolved in benzene andchromatographed on 200 g. of 60-100 mesh magnesium silicate, elutingfirst with benzene and then benzene with increasing amounts of acetone.At 25% acetone-benzene pure product was obtained as a glassy solid;yield 4.2 g. (74%).

Analysis.--Calculated for C₂₄ H₂₉ N₃ O₅ (percent): C, 65.58; H, 6.65; N,9.56. Found (percent); C, 65.34; H, 6.86; N, 9.57.

EXAMPLE 63-{2-[3-(4-methoxyphenylcarbamoyloxy)-pyrrolidinyl]ethyl}indole

A stirred suspension of 3.5 g. (0.015 mole) of3-[2-(3-hydroxypyrrolidinyl)ethyl]indole in 50 ml. of dry benzene wastreated dropwise with 2.3 g. (0.015 mole) of p-methoxyphenylisocyanatein 15 ml. of dry benzene. After addition (0.5 hour) the mixture wasrefluxed for 12 hours after which time only a small amount of solidremained suspended. The residue was filtered off and the filtrate wasevaporated under vacuum to an orange gum. The product was dissolved inbenzene and chromatographed on 200 g. of 60-100 mesh magnesium silicate,eluting first with benzene then benzene with increasing amounts ofacetone. At 20% acetone-benzene pure product was obtained from thecolumn; yield 3.5 g. (60%). The glassy solid would not crystallize.

Analysis.--Calculated for C₂₂ H₂₅ N₃ O₃ (percent): C, 69.63; H, 6.64; N,11.07. Found (percent): C, 69.35; H, 6.76; N, 11.12.

EXAMPLE 7 5,6-dimethoxy-3-[2-(3-hydroxypyrrolidinyl)ethyl]indolehydrochloride monohydrate

A mixture of 5.5 g. (0.017 mole) of1-[(5,6-dimethoxyindol-3-yl)glyoxyloyl] - 3-pyrrolidinol in 50 ml. ofdry tetrahydrofuran was added dropwise to a stirred suspension of 2.85g. (0.075 mole) of lithium aluminum hydride in 100 ml. oftetrahydrofuran under nitrogen. After addition the mixture was refluxedfor 4 hours, cooled in ice and treated with a saturated sodium sulfatesolution. The inorganic salts were removed by filtration and washedthoroughly with tetrahydrofuran. The filtrates were evaporated underreduced pressure yielding 4 g. of crude product. Although separation ofthe pure material from its impurities could be effected using partitionchromatography on thin-layer plates, several attempts using largeramounts on a column failed.

The remaining crude product (2 g.) was dissolved in isopropanol andtreated with ethereal hydrogen chloride. After standing several days inthe cold the dark gray amorphous solid was filtered off, washed withether and air dried. The product decomposed slowly about 95° C. and wasshown to be a monohydrate by analysis; yield 0.7 g.

Analysis.--Calculated for C₁₆ H₂₅ ClN₂ O₄ (hydrate) (percent): C, 55.72;H, 7.30. Found (percent): C, 56.50; H, 7.18.

Analysis.--Calculated for C₁₆ H₂₃ ClN₂ O₃ (dried at 100°) (percent): C,58.80; H, 7.09; N, 8.57. Found (percent): C, 59.09; H, 6.96; N, 8.29.

EXAMPLE 8 3-{2-[3-(o-methoxyphenoxy)pyrrolidinyl]ethyl} indolehydrochloride

A solution of 13.5 g. (0.037 mole) of 1-(indole-3-ylglyoxyloyl)-3-(o-methoxyphenoxy)pyrrolidine in 50 ml. ofanhydrous tetrahydrofuran was added dropwise to a stirred slurry of 7 g.(0.18 mole) of lithium aluminum hydride in 150 ml. of anhydroustetrahydrofuran. The reaction mixture was worked up in the usual mannerand the oily basic material which was isolated was dissolved in etherand treated with ethereal hydrogen chloride. The isolated hydrochlorideweighed 10.7 g. (73%) and melted with decomposition (gas evolution) neara55° C. as a result of solvated ether. Thin layer chromatography of asample of regenerated free base showed a single spot.

Analysis.--Calculated for C₂₁ H₂₅ ClN₂ O₂ (percent): C, 67.64; H, 6.76;N, 7.51. Found (after drying at 120°) (percent): C, 67.72; H, 7.07; N,7.43.

EXAMPLE 9 3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indole

Twenty-two and four-tenths grams (0.066 mole) of1-(indol-3-ylglyoxyloyl)-4-phenyl- 3,4-dehydropiperidine suspended in100 ml. of tetrahydrofuran was added dropwise to a stirred suspension of10.1 g. (0.27 mole) of lithium aluminum hydride in 300 ml. oftetrahydrofuran under a nitrogen atmosphere. The reaction mixture wasrefluxed three hours, cooled, and the excess metal hydride decomposedcautiously by the addition of ice. The mixture was filtered free ofinorganic salts and the filtrate conentrated to an oil which solidifiedon standing. Three recrystallizations of the impure solid (M.P.132°-134° C.) from benzene-isooctane gave 7.2 g. (36%) of pure productmelting at 138°-140° C.

Analysis.--Calculated for C₂₁ H₂₂ N₂ (percent): C, 83.40; H, 7.33; N,9.26. Found (percent): C, 83.45; H, 7.38; N, 9.17.

EXAMPLE 10 2-methyl-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl] indole

Using the method of Example 9, 18.3 g. (0.053 mole) of1-[(2-methylindol-3-yl)glyoxyloyl] - 4-phenyl-3,4-dehydropiperidine wasreduced using 10.1 g. (0.266 mole) of lithium aluminum hydride to give3.9 g. of 2-methyl-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indolemelting at 142°-144° C.

Analysis.--Calculated for C₂₂ H₂₄ N₂ (percent): C, 83.50; H, 7.65; N,8.85. Found (percent): C, 83.47; H, 7.54; N, 8.81.

EXAMPLE 11 5-chloro-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl] indole

Using the method of Example 9, 10.0 g. (0.0274 mole) of1-[(5-chloroindol-3-yl)glyoxyloyl] - 4-phenyl-3,4-dehydropiperidine wasreduced using 5.2 g. (0.137 mole) of lithium aluminum hydride to give6.3 g. of 5-chloro-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indolemelting at 166°-169° C. Recrystallization from benzene raised themelting point to 168°-170° C.

Analysis.--Calculated for C₂₁ H₂₁ ClN₂ (percent): C, 74.87; H, 6.28; N,8.32. Found (percent): C, 75.10; H, 6.20; N, 8.26.

EXAMPLE 12 2,5-dimethyl-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indole

Using the method of Example 9, 8.0 g. (0.0224 mole) of1-[(2,5-dimethylindol-3-yl)glyoxyloyl] - 4-phenyl-3,4-dehydropiperidinewas reduced using 4.25 g. (0.112 mole) of lithium aluminum hydride togive 4.5 g. (61%) of 2,5 -dimethyl-3-[ 2 -(4-phenyl-3,4-dehydroperidinyl)ethyl]indole which melted at 150°-152° C. afterrecrystallization from benzene.

Analysis.--Calculated for C₂₃ H₂₀ N₂ (percent): C, 83.59; H, 7.93; N,8.48. Found (percent): C, 83.38; H, 7.92; N, 8.72.

EXAMPLE 13 5,6-dimethoxy-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indole

Using the method of Example 9, 6.9 g. (0.0177 mole) of 1-[5,6-dimethoxyindol-3 -yl)glyoxyloyl]-4-phenyl-3,4-dehydropiperidine wasreduced using 3.36 g. (0.0885 mole) of lithium aluminum hydride to givea crude oil which was purified by chromatography to give 1.3 g. of5,6-dimethoxy-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl] indolemelting at 125°-127° C.

Analysis.--Calculated for C₂₃ H₂₆ N₂ O₂ (percent): C, 76.21; H, 7.23; N,7.73. Found (percent): C, 75.78; H, 7.14; N, 7.97.

EXAMPLE 145,6-dimethoxy-2-methyl-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indole

Using the method of Example 9, 17 g. (0.0353 mole) of1-[(5,6-dimethoxy-2-methylindol-3-yl)glyoxyloyl]-4-phenyl-3,4-dehydropiperidine was reduced using 6.8 g.(0.176 mole) of lithium aluminum hydride to give 8.1 g. of5,6-dimethoxy-2-methyl-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indolemelting at 116°-118° C. Recrystallization from benzene-isooctane raisedthe melting point to 117°-118° C.

Analysis.--Calculated for C₂₄ H₂₈ N₂ O₂ (percent): C, 76.56; H, 7.50; N,7.44. Found (percent): C, 76.17; H, 7.40; N, 7.50.

EXAMPLE 15 5-benzyloxy-3-[2-(4-hydroxy-4-phenylpiperidinyl)ethyl] indolehydrochloride

Using the method of Example 9, 30 g. (0.066 mole) of1-[(5-benzyloxyindol-3-yl)glyoxyloyl]-4-hydroxy-4-phenylpiperidine wasreduced using 12.5 g. (0.33 mole) of lithium aluminum hydride to give 30g. of 5-benzyloxy-3-[2-(4-hydroxy-4-phenylpiperidinyl)ethyl]indole. Thehydrochloride salt was prepared and after recrystallization fromisopropanol melted at 208°-210° C. The yield was 25.5 g. (83%).

Analysis.--Calculated for C₂₈ H₃₁ ClN₂ O₂ (percent): C, 72.63; H, 7.66;N, 6.05. Found (percent): C, 72.63; H, 6.88; N, 5.90.

EXAMPLE 16 5-hydroxy-3-[2-(4-hydroxy-4-phenylpiperidinyl)ethyl] indole

A solution of 10 g. of5-benzyloxy-3-[2-(4-hydroxy-4-phenylpiperidinyl)ethyl]indole in 10 ml.of ethanol was shaken on the Parr apparatus at room temperature at aninitial pressure of 50 p.s.i., using a 10% palladium on charcoalcatalyst. After debenzylation was complete the solution was filtered andthe catalyst washed thoroughly with three 100 ml. portions of hotethanol. Concentration of the original filtrate gave 3 g. of an oilwhich solidified and was recrystallized from ethyl acetate-methanol togive 1.85 g. of material which melted at 150° C., resolidified andmelted again at 235°-240° C. The combined alcohol washes onconcentration gave 4 g. of a white solid which after recrystallizationfrom ethyl acetate-methanol gave 3.4 g. of material which melted at 150°C., recrystallized and melted again at 235°-240° C. A nuclear magneticresonance spectrum indicated the above solids to be solvated withmethanol. A sample was dried in vacuo at 110° for 24 hours; the driedsample melted at 238°-240° C.

Analysis.--Calculated for C₂₁ H₂₅ ClN₂ O₂ (percent): C, 67.64; H, 6.76;N, 7.51. Found (percent): C, 67.29; H, 6.87; N, 7.54.

EXAMPLE 17 3-[2-(4-hydroxy-4-phenylpiperidinyl)ethyl]indole

A solution of 17.0 g. (0.049 mole) of1-(indol-3-ylglyoxyloyl)-4-phenyl-4-piperidinol in 100 ml. oftetrahydrofuran was reduced in the usual way with 7.4 g. (0.195 mole) oflithium aluminum hydride in 200 ml. of tetrahydrofuran. After the usualworkup 11.6 g. of oil was obtained which was crystallized frombenzene-isooctane yielding 8.6 g. (55%) of product which melted at133°-137° C. Another recrystallization from benzene raised the meltingpoint to 137°-139° C. The analytical sample melted at 137°-139° C.

Analysis.--Calculated for C₂₁ H₂₄ N₂ O (percent): C, 78.71; H, 7.55; N,8.74. Found (percent): C, 78.30; H, 7.36; N, 8.60.

EXAMPLE 18 3-[2-(4-phenyl-4-propionyloxypiperdinyl)ethyl]indole

A mixture of 4 g. (0.0125 mole) of3-[2-(4-hydroxy-4-phenylpiperidinyl)ethyl]indole, 1.19 g. (0.0125 mole)of propionyl chloride and 7 g. of potassium carbonate in 50 ml. ofchloroform was allowed to stir for 2 hours. Then 0.4 g. of additionalpropionyl chloride was added and allowed to stir another 30 minutes. Themixture was treated with 50 ml. of water and allowed to stir 30 minutes.The chloroform layer was separated, dried over magnesium sulfate andevaporated under reduced pressure to an oil. The oil was crystallizedfrom benzene-isooctane and yielded 3.0 g. (64%) of product which meltedat 140°-142° C. After an additional recrystallization the analyticalsample melted at 142°-144° C.

Analysis.--Calculated for C.sub. 24 H₂₈ N₂ O₂ (percent): C, 76.56; H,7.50; N, 7.44. Found (percent): C, 76.52; H, 7.47; N, 7.44.

EXAMPLE 19 3-[2-(4-hydroxy-4-m-trifluoromethylphenylpiperidinyl)ethyl]indole hydrochloride

A solution of 37 g. (0.089 mole (of 1-(indol-3-ylglyoxyloyl)-4-(m-trifluoromethylphenyl)-4-piperidinol in 100 ml. oftetrahydrofuran was added dropwise under nitrogen to a stirredsuspension of 16.9 g. (0.445 mole) of lithium aluminum hydride in 100ml. of tetrahydrofuran. The reaction was refluxed two hours and thenworked up in the usual manner. Recrystallization of the isolated solidfrom benzene-isooctane gave 26.5 g. (70%) of pure product which wasshown by nuclear magnetic resonance to be a benzene solvate. A portionof the free base was converted to the hydrochloride salt which melted at244°-246° C. after crystallization from isopropanol containing a smallamount of methanol.

Analysis.--Calculated for C₂₂ H₂₄ ClF₃ N₂ O (percent): C, 62.19; H,5.69; N, 6.59. Found (percent): C, 62.55; H, 6.13; N, 6.40.

EXAMPLE 203-[2-(4-propionyloxy-4-m-trifluoromethylphenylpiperidinyl)ethyl]indolehydrochloride

A mixture of 10 g. (0.0234 mole) of 3-[2-(4-hydroxy-4-m-trifluoromethylphenylpiperidinyl)ethyl]indole, 20 g. of potassiumcarbonate, 2.48 g. (0.0258 mole) of propionyl chloride and 100 ml. ofchloroform was stirred four hours at room temperature. An additional 2.0g. of propionyl chloride was added and the mixture allowed to stirovernight at room temperature. The reaction mixture was treated with 80ml. of water and 20 ml. of 3 N sodium hydroxide, stirred 0.5 hour andthe layers separated. Concentration of the organic layer gave 9.0 g. ofoil which was converted to the hydrochloride salt. Recrystallization ofthe salt from isopropanol-isopropyl ether gave 7.6 g. (68%) of productmelting at 169°-172° C.

Analysis.--Calculated for C₂₅ H₂₈ ClF₃ N₂ O₂ (percent): C. 62.43; H,5.87; N, 5.83. Found (percent): C, 62.58; H, 5.89; N, 6.02.

EXAMPLE 213-[2-(4-m-trifluoromethylphenyl-3,4-dehydropiperidinyl]ethyl]indole

Ten grams (0.0234 mole) of3-[2-(4-hydroxy-4-m-trifluoromethylphenylpiperidinyl)ethyl]indolebenzene solvate was refluxed 24 hours under nitrogen with 75 ml. of 2:1glacial acetic acid-concenrated hydrochloric acid. The cooled mixturewas neutralized with 3 N sodium hydroxide and the aqueous mixtureextracted with chloroform. The combined extracts were dried andconcentrated to an oil which solidified. The crude solid was dissolvedin a minimum amount of benzene and was chromatographed using 300 g. ofmagnesium silicate. The product was eluted with acetone-benzene and at10% acetone-benzene pure product began to be eluted. Elution began todiminish at 65% acetone-benzene. Six grams of solid was isolated fromwhich 4.3 g. (49%) of product melting at 152°-154° C. was obtained aftercrystallization from benzene-isooctane.

Analysis.--Calculated for C₂₂ H₂₁ F₃ N₂ (percent): C, 71.33; H, 5.71; N,7.56. Found (percent): C, 71.52; H, 5.71; N, 7.89.

EXAMPLE 22 1-methyl-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indolehydrochloride

To a gently refluxing solution of 3 g. (0.01 mole) of 3-[2-(4-phenyl-3,4-dehydropiperidinyl(ethyl]indole in 50 ml. of acetone wasadded all at once 7.5 g. of powdered KOH followed immediately by 1.39 g.(0.01 mole) of methyl iodide in 25 ml. of acetone, added dropwise. Afterstirring 5 minutes at reflux the mixture was cooled and filtered. Thefiltrate was evaporated to an oil which was dissolved in chloroform.After washing with water the chloroform solution was dried overmagnesium sulfate and evaporated to an oil. The impure product, 3.4 g.,was dissolved in benzene and chromatographed on 150 g. of 60-100 meshmagnesium silicate eluting with benzene containing increasing amounts ofacetone. The purified oil was dissolved in ether and treated withethereal HCl. The resulting salt melted at 217°-220° C. afterrecrystallization from isopropanol. The analytical sample melted at219°-222° C.

Analysis.--Calculated for C₂₂ H₂₅ ClN₂ (percent): C, 74.87; H, 7.14; N,7.94. Found (percent): C, 74.67; H, 7.26; N, 8.09.

EXAMPLE 23 3-[2-(4-p-fluorophenyl-3,4-dehydropiperidinyl)ethyl]indole

A suspension of 8.9 g. (0.0256 mole) of 1-(indol-3-ylglyoxyloyl)-4-(p-fluorophenyl)-3,4-dehydropiperidine in 50 ml. of tetrahydrofuranwas added slowly to a stirred suspension of 4.85 g. (0.13 mole) oflithium aluminum hydride in 50 ml. of tetrahydrofuran. The stirredmixture was allowed to reflux under an atmosphere of nitrogen for 2hours then worked up in the usual way. The crude crystalline product wasrecrystallized from benzene and yielded 3.6 g. (48%) of product whichmelted at 156°-158° C. The analytical sample was recrystallized frombenzene and melted at a157°-159° C.

Analysis.--Calculated for C₂₁ H₂₁ FN₂ (percent): C, 78.72; H, 6.61; N,8.74. Found (percent): C, 79.04; H, 6.74; N, 8.60.

Utilizing the process of Example 1, the following compounds are preparedfrom the stated starting materials:

1 -phenyl- 3-[2-(4-benzyl-4-hydroxypiperidinyl)ethyl] indole by reacting1-[(1-phenylindol-3-yl)glyoxyloyl]-4-benzyl-4-piperidinol with lithiumaluminum hydride.

1 -benzyl- 3-[2-(4-hydroxy-3-methyl-4-phenylpiperidinyl)ethyl]indole byreacting 1 -[ (1-benzylindol-3-yl)glyoxyl]-3-methyl-4-phenyl-4-piperidinol with lithium aluminumhydride.

1 -cyclohexyl- 3-[2-(4-hydroxy-3-methyl-4-phenylpiperidinyl)ethyl]indole by reacting1-[(1-cyclohexyl-3-yl) glyoxyloyl]-3-methyl-4-phenyl-4-piperidinol withlithium aluminum hydride.

3 -[2-(4-hydroxy-4-o-tolylpiperidinyl)ethyl]indole by reacting 1-(indol-3-ylglyoxyloyl)-4-o-tolyl-4-piperidinol with lithium aluminumhydride.

3 -[2-(4-hydroxy-3-methyl-4-o-tolylpiperidinyl)ethyl]indole by reacting1-(indol-3-ylglyoxyloyl)-3-methyl-4-o-tolyl-4-piperidinol with lithiumaluminum hydride.

6 -trifluoromethyl-3-[2-(4-hydroxy-4-phenylpiperdinyl)ethyl]indole byreacting1-[(6-trifluoromethylindol-3-yl)glyoxyloyl]-4-phenyl-4-piperidinol withlithium aluminum hydride.

2 -phenyl- 3-[2-(4-hydroxy-4-phenylpiperidinyl)ethyl]indole by reacting1-[(2-phenylindol-3-yl)glyoxyloyl]-4-phenyl-4-piperidinol with lithiumaluminum hydride.

EXAMPLE 24 1-benzoyl-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl] indole

A solution of 30 g. (0.1 mole) of3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indole in 75 ml. ofdimethylformamide is added dropwise to a stirred slurry of 4.8 g. (0.1mole) of sodium hydride (50% suspension in mineral oil) in 50 ml. ofdimethylformamide maintained at 10° C. After stirring one hour 14.0 g.(0.1 mole) of benzyl chloride is added dropwise, the reaction mixturebeing maintained at 5°-10° C. After addition the reaction mixture isstirred several hours at room temperature and then poured into twovolumes of cold water. The precipitated product is collected by suctionfiltration and dried.

EXAMPLE 25 1-propionyl-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indole

To a stirred slurry of 4.8 g. (0.1 mole) of sodium hydride (50%suspension in mineral oil) in 75 ml. of dimethylformamide maintained at5°-10° C. is added dropwise a solution of 30 g. (0.1 mole) of3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl indole. The mixture isstirred two hours and is treated dropwise at 5°-10° C. with 10 g. (0.1mole) of propionyl chloride. The reaction mixture is stirred four hoursat room temperature and is then added to two volumes of cold water. Theprecipitated product is collected by suction filtration.

EXAMPLE 26 1-methyl-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl] indolemethoiodide

A mixture of 5.0 g. of1-methyl-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indole and 5.0 ml.of methyl iodide is warmed for a minute and then cooled in an ice bathwith scratching with a glass rod to induce crystallization. Thequaternary salt which separates is collected and dried.

Pharmacology

The compounds of the present invention were screened foranti-Parkinsonism and were observed to be effective in eliminating thepronounced symptom complex of tremor, motor incoordination, lacrimationand catatonia. 4-methoxyphenethylamine is excreted by Parkinsonpatients, indicating the diseased state to be associated with anabnormality of the normal process by which certain biogenic amines aremethylated. Injection of 4-methoxyphenethylamine into laboratory animalsresults in the syndrome of Partkinsonism. The efficacy of the novelcompounds was determined by administering each of them to groups of fivemice. One hour later 4-methoxyphenethylamine was givenintraperitoneally. The mice were observed for the symptoms ofParkinsonism and a drug's effectiveness was determined by the completeprevention of tremor, motor incoorination, lacrimation and catatonia.The ED₅₀ of each drug was determined by the injection of appropriatenumber of doses and subjecting the results to probit analysis accordingto the method of J. T. Litchfield and F. Wilcoxon, J. Pharm. and Exptl.Therap. 96, 99 (1949).

Formulation and administration: Effective quantities of any of theforegoing pharmacologically active compounds may be administered to aliving animal body in any one of various ways, for example, orally as incapsules or tablets, parenterally in the form of sterile solutions orsuspensions, and in some cases intravenously in the form of sterilesolutions. The free basic amino compounds, while effective, arepreferably formulated and administered in the form of their non-toxicacid-addition or quaternary ammonium salts for purposes of convenienceof crystallization, increased solubility, and the like.

Although very small quantities of the active materials of the presentinvention, even as low as 0.1 milligram, are effective when minortherapy is involved or in cases of administration to subjects having arelatively low body weight, unit dosages are usually five milligrams orabove and preferably twenty-five, fifty or one-hundred milligrams. Fiveto fifty milligrams appears optimum per unit dose, while usual broaderranges appear to be one to 500 milligrams per unit dose. The activeagents of the invention may be combined with other Pharmacologicallyactive agents, or with buffers, antacids or the like, for administrationand the proportion of the active agent in the compositions may be variedwidely. It is only necessary that the active ingredient constitute aneffective amount, i.e., such that a suitable effective dosage will beobtained consistent with the dosage form employed. Obviously, severalunit dosage forms may be administered at about the same time. The exactindividual dosages as well as daily dosages in a particular case will ofcourse be determined according to established medical principles underthe direction of a physician or veterinarian. Results uponadministration of these novel materials have thus far proved extremelygratifying.

Examples of compositions within the preferred ranges given are asfollows:

    ______________________________________                                        Capsules                                                                      ______________________________________                                        Ingredients:       Per cap., mg.                                              ______________________________________                                        (1) Active ingredient, as salt                                                                    25,000                                                    (2) Lactose        146,000                                                    (3) Magnesium stearate                                                                            4,000                                                     ______________________________________                                    

Procedure:

(1) Blend 1, 2 and 3.

(2) Mill this blend and blend again.

(3) This milled blend is then filled into No. 1 hard gelatin capsules.

    ______________________________________                                        Tablets                                                                       ______________________________________                                        Ingredients:       Mg./tab.,                                                  ______________________________________                                        (1) Active ingredient, as salt                                                                   25.0                                                       (2) Corn starch    20.0                                                       (3) Alginic acid   20.0                                                       (4) Sodium alginate                                                                              20.0                                                       (5) Magnesium stearate                                                                           1.3                                                        ______________________________________                                    

Procedure:

(1) Blend 1, 2, 3 and 4.

(2) Add sufficient water portionwise to the blend from step No. 1 withcareful stirring after each addition. Such additions of water andstirring continue until the mass is of a consistency to permit itsconversion to wet granules.

(3) The wet mass is converted to granules by passing it through theoscillating granulator, using 8-mesh screen.

(4) The wet granules are then dried in an oven at 140° F.

(5) the dried granules are then passed through an oscillatinggranulator, using a 10-mesh screen.

(6) Lubricate the dry granules with 0.5% magnesium stearate.

(7) The lubricated granules are compressed on a suitable tablet press.

    ______________________________________                                        Intramuscular injection                                                       ______________________________________                                        Ingredients:        Per ml.                                                   ______________________________________                                        (1) Active ingredient, as salt                                                                    25.0 mg.                                                  (2) Isotonic buffer solution 4.0                                                                  Q.s. to 2.0 ml.                                           ______________________________________                                    

Procedure:

(1) Dissolve the active ingredient in the buffer solution.

2) Aseptically filter the solution from step No. 1.

(3) The sterile solution is now aseptically filled into sterileampoules.

(4) The ampoules are sealed under aseptic conditions.

Various modifications and equivalents will be apparent to one skilled inthe art and may be made in the compounds, methods, compositions, andprocedures of the present invention without departing from the spirit orscope thereof, and it is therefore to be understood that the inventionis to be limited only by the scope of the appended claims.

What is claimed and desired to be secured by U.S. Letters Patents is: 1.A member selected from the group consisting of compounds having theformula: ##SPC2##and pharmaceutically acceptable acid addition saltsthereof, wherein; R₁ is selected from the group consisting of hydrogenand lower alkyl; R₁ is selected from the group consisting of hydrogen,lower alkyl and phenyl; R₂ is selected from the group consisting ofhydrogen, fluoro, chloro, bromo, lower-alkyl and lower-alkoxy; and R₄ isselected from the group consisting of benzyl, phenyl andmono-substituted phenyl in which the substituent is selected from thegroup consisting of fluoro, chloro, bromo, lower-alkyl andtrifluoromethyl.
 2. A compound selected from the group consisting of afree base and its pharmaceutically acceptable acid addition andquaternary ammonium salts, the free base having the structural formula:##SPC3##wherein: R is selected from the group consisting of hydrogen,lower-alkyl, lower-alkanoyl, benzoyl, benzyl, and cycloalkyl containingthree to nine carbon atoms inclusive; R₁ is selected from the groupconsisting of hydrogen, lower-alkyl, and phenyl; R₂ is selected from thegroup consisting of hydrogen, halogen of atomic weight less than 80,trifluoromethyl, hydroxyl, lower-alkyl, lower-alkoxy, and benzyloxy; nis an integer from zero to four inclusive; Sub is a member selected fromthe group consisting of ##SPC4##wherein; A is selected from the groupconsisting of hydrogen, 3,4,5-trimethoxybenzoyl,3,4,5-trimethoxyphenylcarbamoyl, p-methoxycarbamyol, and2-methoxyphenyl; R⁵ is a member selected from the group consisting ofbenzyl, phenyl and monosubstituted phenyl in which the substituent isselected from the group consisting of lower-alkyl, trifluoromethyl, andhalogen of atomic weight less than 80, and R⁶ is selected from the groupconsisting of trifluoromethyl and halogen of atomic weight less than 80.3. A compound of claim 2 which is3-[2-(3-hydroxypyrrolidinyl)ethyl]indole.
 4. A compound of claim 2 whichis2-methyl-3-{2-[3-(3,4,5-trimethyoxybenzoyloxy)pyrrolidinyl]ethyl]}indole.5. A compound of claim 2 which is2-methyl-3-[2-(3-hydroxypyrrolidinyl)ethyl]indole hydrochloride.
 6. Acompound of claim 2 which is3-{2-[3-(3,4,5-trimethoxybenzoyloxy)pyrrolidinyl]ethylene]}indole.
 7. Acompound of claim 2 which is3-{2-[3-(3,4,5-trimethoxyphenylcarbamoyloxy)pyrrolidinyl] ethyl]}indole.8. A compound of claim 2 which is5,6-dimethoxy-3-[2-(3-hydroxypyrrolidinyl)ethyl]indole hydrochloride. 9.A compound of claim 2 which is3-{2-[3-(o-methoxyphenoxy)pyrrolidinyl]ethyl]}indole hydrochloride. 10.A compound of claim 2 which is3-{2-[3-(4-methoxyphenylcarbamoyloxy)pyrrolidinyl]ethyl]}indole.
 11. Acompound of claim 2 which is3-[2-(4-hydroxy-4-phenylpiperidinyl)ethyl]indole.
 12. .[.A compound ofclaim 2 which is.]. 3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indole.13. .[.A compound of claim 2 which is.].2-methyl-3[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indole.
 14. .[.Acompound of claim 2 which is.].2-methyl-5,6-dimethoxy-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indole.15. .[.A compound of claim 2 which is.].5-chloro-3[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indole.
 16. Acompound of claim 2 which is5-benzyloxy-3-[2-(4-hydroxy-4-phenylpiperidinyl)ethyl]indolehydrochloride.
 17. A compound of claim 2 which is5-hydroxy-3-[2-(4-hydroxy-4-phenylpiperidinyl)ethyl]indole.
 18. .[.Acompound of claim 2 which is.].5,6-dimethoxy-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indole. 19..[.A compound of claim 2 which is.].2,5-dimethyl-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indole.
 20. Acompound of claim 2 which is3-[2-(4-hydroxy-4-m-trifluoromethylphenylpiperidinyl)ethyl]indolehydrochloride.
 21. A compound of claim 2 which is3-[2-(4-m-trifluoromethylphenyl-3,4-dehydropiperidinyl)ethyl]indole. 22..[.A compound of claim 2 which is.].1-methyl-3-[2-(4-phenyl-3,4-dehydropiperidinyl)ethyl]indol
 23. Acompound of claim 2 which is3-[2-(4-p-fluorophenyl-3,4-dehydropiperidinyl)ethyl]indole.
 24. Acompound selected from the group having the formula: ##SPC5##wherein; Ris selected from the group consisting of hydrogen, lower-alkyl, benzyl,and cycloalkyl containing three to nine carbon atoms inclusive; R₁ isselected from the group consisting of hydrogen, lower-alkyl and phenyl;R₂ is selected from the group consisting of hydrogen, halogen of atomicweight less than 80, trifluoromethyl, hydroxyl, lower-alkyl,lower-alkoxy and benzyloxy; n is an integer from zero to fourinclusive;Sub is a member selected from the group consisting of ##SPC6##wherein; R₅ is a member selected from the group consisting of benzyl,phenyl and monosubstituted phenyl in which the substituent is selectedfrom the group consisting of lower-alkyl, trifluoromethyl, and halogenof atomic weight less than 80, and R₆ is selected from the groupconsisting of trifluoromethyl and halogen of atomic weight less than 80.